Proper function of voltage gated potassium channels (Kv) is vital to health and disease, as demonstrated by identification of mutations in genes that encode Kv channel subunits as causing cardiac and neurological disorders in humans. Potassium (K) channels have key roles in the regulation of neuronal excitability. Over a hundred different subunits encoding distinct K channel subtypes have been identified so far. However, relating these many different channel subunits to the functional K currents observed in native neurons remains a major challenge. Thus, identifying the native composition of macromolecular potassium channel complexes is a critical step to understand the regulation and function of native K currents. Kv2.1 is a major subunit encoding delayed rectifier potassium currents in neurons. Recently, Kv2.1 has been proposed to be involved in neuronal apoptosis. The objective of this proposal is biochemical purification of the native Kv2.1 channel multi-protein complex and the analysis of the molecular components of the Kv2.1 channel complex by proteomic approach. Completion of the proposed research will identify Kv2.1-associated proteins, which provides insights into the mechanism of current diversity and the regulation of neuronal delayed rectifier potassium currents.